The goal of this program project remains fixed on understanding the etiology and pathogenesis of demyelinating and chronic degenerative diseases of the nervous system. The hypothesis tested is that many such human disorders, like multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and other progressive CNS disorders, are likely caused by a persisting virus infection and/or aberrant immune response(s) against the virus and/or host self antigens. Our strategy is utilization of both in vitro studies and experimental animal models to shed information towards understanding and treating human CNS disease. Hence, the approaches followed are understanding (1) molecular and cellular mechanisms of viral tropism for cells of the nervous and immune systems; (2) means by which viruses regulate their genes to persist in infected cells (go from lytic to non-lytic phenotype), escape immune surveillance and alter normal cell's physiologic (differentiated) functions; (3) humoral and cellular (cytotoxic T cell) immune responses serving to eliminate infectious agents and lyse infected cells to prevent viral persistence; (4) environmental and genetic factors enhancing susceptibility to virus infection and injury, and causing aberrant immune responses; (5) the molecular and cellular events that mediate viral and/or immune destruction of cells and tissues leading to demyelinating and degenerative disease; (6) functional-structural (crystallographic) correlates that define why viruses are tropic and demyelinative for CNS cells. This program blends the skills of investigators with expertise in experimental medicine and pathology, neurologic diseases, immunology, virology, molecular biology, biochemistry, cell biology, molecular genetics and x-ray crystallography. By this means a focussed attack is made on understanding the cause, pathogenesis and hopefully therapeutic approaches to preventing demyelinating and degenerative disorders of the nervous system.